KR100499903B1 - 5ht2 agonists for controlling iop and treating glaucoma - Google Patents

Abstract

Disclosed are compositions and methods for intraocular pressure control and glaucoma treatment using 1- (2-aminopropyl) -indazol-6-ol.

Description

5HTH2 Agonist for Intraocular Pressure Control and Glaucoma Treatment {5HTT AGONISTS FOR CONTROLLING IOP AND TREATING GLAUCOMA}

The present invention relates to the reduction and control of intraocular pressure (IOP) and the use of 1- (2-aminopropyl) -indazol-6-ol for the treatment of glaucoma.

A disease state called glaucoma is characterized by permanent loss of vision due to irreversible damage to the optic nerve. Some morphological or functional types of glaucoma are characterized by increased IOP, which is believed to be associated as a cause for the pathological course of the disease. Ocular hypertension results in elevated intraocular pressure but no visible visual impairment; These patients are considered to be at high risk of consequent visual impairment associated with glaucoma. Some patients with glaucoma visual field defects have relatively low intraocular pressure. These so-called patients with normal or low pressure glaucoma may benefit from drugs that reduce and control IOP.

If glaucoma or ocular pressure is detected early and treated quickly with medication that effectively reduces elevated intraocular pressure, vision impairment or progressive deterioration can generally be improved. Drug therapies that have been shown to be effective in reducing intraocular pressure include both drugs that reduce the production of aqueous fluids and drugs that promote waterproofing. Such therapeutic agents are generally administered in one of two routes: external (direct application to the eye) or oral administration.

There are patients who do not respond well when treated with certain existing glaucoma therapies. Therefore, there is a need for other external therapeutic agents that control IOP.

The compound, 1- (2-aminopropyl) -indazol-6-ol, is disclosed in WO98 / 30548. Example 46 in this application discloses S-enantiomers of 1- (2-aminopropyl) -indazol-6-ol. The use referred to in this application is the treatment of central nervous system diseases such as sexual dysfunction, fertility, appetite control disorders, anxiety, depression and sleep disorders. Ophthalmic use has not been disclosed.

Summary of the Invention

The present invention relates to compositions of 1- (2-aminopropyl) -indazol-6-ol and its use for reducing and controlling IOP and for treating glaucoma.

Description of Preferred Embodiments

Surprisingly, 1- (2-aminopropyl) -indazol-6-ol ("present compound") and its S-(+)-isomers, when administered at 300 μg, are in a monkey model with a high ocular laser It has been found that this leads to a significant decrease in IOP, as shown in the table defined below. Intraocular pressure is determined by Alcon Pneumatometer after light corneal anesthesia with 0.1% proparacaine. After each measurement the eyes were washed with saline. After the baseline IOP measurement, 30 μL aliquots of the test compound were instilled into the right eye of nine chinomolgus monkeys. Medium was added to the right eye of six additional animals. Subsequent IOP measurements were made at 1, 3 and 6 hours. If there is a reduction of at least 20% in the baseline IOP of the laser shot eye (O.D.) following external administration, the compound is considered to have an effect on the ocular pressure of this model.

IOP reaction to 1- (2-aminopropyl) -indazol-6-ol and its S (+)-isomer

Capacity (μg) Reference IOP (mmHg) IOP response% change (△ mmHg) 1 hours 3 hours 6 hours compound 300 40.1 -17.6 (7.3) -28.1 (11.8) -33.8 (14.6) media 40.5 -6.5 (3.0) -13.6 (5.7) -8.1 (3.8) S-(+)-isomer 300 40.3 -15.0 (6.4) -35.3 (14.8) -40.8 (17.1) media 38.0 -3.1 (1.8) -6.8 (3.3) -4.7 (2.8)

S-isomers of 1- (2-aminopropyl) -indazol-6-ol are preferred isomers for use in reducing and controlling IOP and treating glaucoma.

The present compounds can be incorporated into various types of ophthalmic preparations that are delivered to the eye (eg, externally, directly applied to the eye or implanted). The compound is preferably incorporated into an external ophthalmic formulation delivered to the eye. The compound is combined with an ophthalmically acceptable preservative, surfactant, viscosity enhancer, permeation enhancer, buffer, sodium chloride, and water to form an aqueous, sterile ophthalmic suspension or solution. Ophthalmic solution formulations may be prepared by dissolving the compound in a physiologically acceptable isotonic aqueous buffer. Furthermore, the ophthalmic solution may comprise an ophthalmically acceptable surfactant that aids in the dissolution of the compound. Furthermore, the ophthalmic solution contains a viscosity increasing agent such as hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose, polyvinylpyrrolidone, etc. to increase the retention of the formulation in the conjunctival sac. can do. Gelling agents include, but are not limited to, gellan and xanthan gum. To prepare sterile ointment formulations, the compounds are combined with preservatives in suitable media such as mineral oil, liquid lanolin or petrolatum. Sterile ophthalmic gel preparations may be prepared by suspending the active ingredient according to known formulation methods for similar ophthalmic preparations in a hydrophilic base prepared with a combination of Carbopol-974 and the like; Preservatives and isotonic agents may be incorporated.

The compound is preferably formulated as an external ophthalmic suspension or solution having a pH of about 5-8. The compound is usually included in these formulations in an amount of about 0.01 to 5% by weight, preferably 0.1 to 2% by weight. Thus, in external application, 1-2 drops of these agents are delivered to the surface of the eye 1 to 4 times per day, as judged by an experienced clinician.

The compound may also be used in combination with other drugs for the treatment of glaucoma. Other drugs include β-blockers (e.g., timolol, betaxolol, levobtaxolol, carteolol, levobonolol, propranolol). , Carbonic anhydrase inhibitors (e.g., brinzolamide and dorzolamide), α1 antagonists (e.g. nipradorol), α2 agonists (e.g., iodidine and brimonidine), pupil shrinkage (Eg, pilocarpine and epinephrine), prostaglandin analogs (eg, latanoprost, travaprost, unoprostone, and US Pat. Nos. 5,889,052; 5,296,504; 5,422,368; and 5,151,444). Compounds, “hypertensive lipids” (e.g., compounds defined in Lumigan and 5,352,708), and neuroprotective agents (e.g., compounds of US Pat. No. 4,690,931, in particular pending US Patent Application No. 06/203350 Eli's prescribed Suitable compounds from WO94 / 13275, including prodyl and R-eliprodil, and memantine, are exemplified, but are not limited thereto.

The following external ophthalmic preparations are useful in accordance with the present invention when administered 1-4 times a day, as judged by an experienced clinician.

Example 1

ingredient Volume (wt%) 1- (2-aminopropyl) -indazol-6-ol (S-(+)-isomer) 0.01-2% Hydroxypropyl methylcellulose 0.5% Dibasic Sodium Phosphate (anhydride) 0.2% Sodium chloride 0.5% Disodium EDTA (Disodium Edit) 0.01% Polysorbate 80 0.05% Benzalkonium Chloride 0.01% Sodium Hydroxide / Hydrochloric Acid Amount required to adjust pH to 7.3-7.4 Purified water Sufficient to be 100%

Example 2

ingredient Volume (wt%) 1- (2-aminopropyl) -indazol-6-ol 0.01-2% Methyl cellulose 4.0% Dibasic Sodium Phosphate (anhydride) 0.2% Sodium chloride 0.5% Disodium EDTA (Disodium Edit) 0.01% Polysorbate 80 0.05% Benzalkonium Chloride 0.01% Sodium Hydroxide / Hydrochloric Acid Amount required to adjust pH to 7.3-7.4 Purified water Sufficient to be 100%

Example 3

ingredient Volume (wt%) 1- (2-aminopropyl) -indazol-6-ol (S-(+)-isomer) 0.01-2% Guar gum 0.4-6.0% Dibasic Sodium Phosphate (anhydride) 0.2% Sodium chloride 0.5% Disodium EDTA (Disodium Edit) 0.01% Polysorbate 80 0.05% Benzalkonium Chloride 0.01% Sodium Hydroxide / Hydrochloric Acid Amount required to adjust pH to 7.3-7.4 Purified water Sufficient to be 100%

Example 4

ingredient Volume (% by weight) 1- (2-aminopropyl) -indazol-6-ol 0.01-2% Vaseline and mineral oil and lanolin Ointment viscosity Dibasic Sodium Phosphate (anhydride) 0.2% Sodium chloride 0.5% Disodium EDTA (Disodium Edit) 0.01% Polysorbate 80 0.05% Benzalkonium Chloride 0.01% Sodium Hydroxide / Hydrochloric Acid Amount required to adjust pH to 7.3-7.4

Claims (13)

delete delete delete delete An external ophthalmic composition for treating glaucoma comprising a pharmaceutically effective amount of 1- (2-aminopropyl) -indazol-6-ol and a pharmaceutically acceptable carrier or diluent. 6. The composition of claim 5 comprising the S-(+)-isomer of 1- (2-aminopropyl) -indazol-6-ol. 6. The composition of claim 5 wherein the concentration of 1- (2-aminopropyl) -indazol-6-ol is from 0.01 to 5% by weight. 8. The composition of claim 7, wherein the concentration is from 0.1 to 2% by weight. The composition of claim 6, wherein the concentration of S-(+)-isomer of 1- (2-aminopropyl) -indazol-6-ol is from 0.01 to 5% by weight. The composition of claim 9 wherein the concentration is from 0.1 to 2% by weight. The composition of claim 5, further comprising one or more other drugs for treating glaucoma. The composition of claim 11, wherein the other drug is selected from the group consisting of β-blockers, carbonic anhydrase inhibitors, α1 antagonists, α2 antagonists, pupil shrinkage agents, prostaglandin analogs, hypotensive lipids, and neuroprotective agents. 13. The drug according to claim 12, wherein the other drug is timolol, betaxolol, levobtaxolol, carteolol, levobunol, propranolol, brinsolamide, dorzolamide, nipradorol, iopidine, brimonidine, A composition which is at least one of pilocarpine, epinephrine, latanoprost, travaprost, unoprostone, lumigan, elliprodil and R-eliprodil.